AM14-PPT-Faden 150226
- 1. 2014 ISPE Annual Meeting How to Implement ASTM E2500 for Legacy Systems Andrew Faden, CPIP Hargrove C+A, Boston, MA October 13, 2014 1
- 2. 2014 ISPE Annual Meeting Agenda • Introductions • Seminal Events in Manufacturing Quality • PV Guidance • E2500 Refresher • Tools for implementing E2500 • Questions? 2
- 3. 2014 ISPE Annual Meeting Introductions My Background • BS Electrical Engineering • MS Bioscience Administration • 20+ years application engineering in high-tech manufacturing – sensors; instruments; industrial control systems; automated equipment • Hi-Rel components and systems, many with impact to life/safety (medical device, aerospace, military) 3
- 4. 2014 ISPE Annual Meeting Introductions My Background • 18 years FSE engineering and project management in pharmaceutical fill-finish manufacturing including liquid fill parenteral, aseptic blow-fill-seal, OSD • CPIP and lots of guidance from ISPE and fellow members! 4
- 5. 2014 ISPE Annual Meeting Introductions Your Background • ISPE members? • Undergrad in engineering? • Work for pharma? • Work for biotech? • Work for vendor? 5
- 6. 2014 ISPE Annual Meeting Introductions Your Background • Quality role? • Engineering role? • Operations role? • Company wants to implement E2500? • Company has implemented E2500? 6
- 7. 2014 ISPE Annual Meeting Seminal Events - Quality • 1924 – Walter Shewhart came up with the concept of common cause and special cause variation to improve the telephone cable manufacturing process. First use of SPC. (ASTM adopted his charts in 1933) • 1939 – Deming introduces new quality concept: • Quality = results/cost • If you focus on decreasing costs, costs rise, and quality falls • If you focus on increasing quality, costs fall, and company results rise – think Apple, Tesla. • Note that the relationship between cost and quality is counterintuitive! 7
- 8. 2014 ISPE Annual Meeting Seminal Events - Quality • 1951 – Juran publishes Quality Control Handbook. – Top management must be involved to effect change – Pareto principle (80/20) – focus on the vital few – Project-by-project approach to quality improvement • 1986 – Bill Smith, Motorola, devised Theory of Latent Defects. Key concept was Six-sigma, a process capability that produces fewer than 3.4 defects per 1,000,000. 8
- 9. 2014 ISPE Annual Meeting Seminal Events – Drug Quality • 2001 – ISPE Baseline Guide Volume 5: Commissioning and Qualification for New and Renovated Facilities: – An engineering approach to provide cost effective facilities in a timely manner. Includes regulated facilities, utilities and equipment. Key concepts: • Impact assessments starting with system, working down to components • Traditional IQ, OQ, PQ verification approach • 2004 – FDA Initiative: Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach – target goals: – Incorporated concepts of risk management and quality systems into the manufacture of pharmaceuticals to encourage innovation and improve product quality 9
- 10. 2014 ISPE Annual Meeting Seminal Events – Drug Quality • 2007 – ASTM E2500 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment. – Applies concepts introduced in Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach – Verification required for acceptance and release of FSE – not validation – Too high-level. Caused confusion. An industry built around validation processes needed more detail 10
- 11. 2014 ISPE Annual Meeting Seminal Events – Drug Quality • 2011 - ISPE GPG Science and Risk-based Approach for the Delivery of Facilities, Systems, and Equipment (FSE Guide). Upgrade of Volume 5 Baseline guide: • Incorporated science and risk based approach for delivery of FES from E2500 • Incorporated QRM concepts from ICH Q8, Q9, and Q10 • Installation, Functional, and Performance Verification; not Validation • Still too vague! • 2011 - ISPE GPG Applied Risk Management for Commissioning and Qualification (ARM Guide) • Describes how organizations can keep same processes (IQ, OQ, PQ) and move from established baseline practice (Volume 5) to a more efficient science- and risk-based framework (FSE) • Wishy-washy, encourages status quo. 11
- 12. 2014 ISPE Annual Meeting Seminal Events – Drug Quality • 2010 to 2015 - ISPE GPG Product Quality Lifecycle Implementation Guide Series (PQLI Guides) - address product and process development and manufacture using science- and risk-based approaches, QbD, QMS. • 2011 - FDA Process Validation: General Principals and Practices (PV Guide). • Update of “Pharmaceutical CGMPs for the 21st Century ― A Risk-Based Approach,” adds use of technology, risk- based approach, and modern quality systems • Ties back to 21CFR 211.100(a) and 21CFR 211.110(a) • References ASTM E2500 and other relevant standards 12
- 13. 2014 ISPE Annual Meeting PV Guide – Key Concepts Start by asking questions: – “…process validation is… the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process. 13
- 14. 2014 ISPE Annual Meeting PV Guide – Key Concepts Iterative process to attain reproducible manufacturing capability: – Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. – Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. – Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. 14
- 15. 2014 ISPE Annual Meeting PV Guide – Key Concepts Current mindset is that things don’t change after process is validated – this is just the beginning! – After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change. 15
- 16. 2014 ISPE Annual Meeting PV Guide – Key Concepts Knowing your process variation is key! • A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that results in products with the desired quality attributes. Manufacturers should: – Understand the sources of variation – Detect the presence and degree of variation – Understand the impact of variation on the process and ultimately on product attributes – Control the variation in a manner commensurate with the risk it represents to the process and product 16
- 17. 2014 ISPE Annual Meeting PV Guide – Key Concepts Once you understand process variation, implement sufficient process controls: • Process controls address variability to assure quality of the product. Controls can consist of material analysis and equipment monitoring at significant processing points (§ 211.110(c)). Decisions regarding the type and extent of process controls can be aided by earlier risk assessments, then enhanced and improved as process experience is gained. 17
- 18. 2014 ISPE Annual Meeting PV Guide – Key Concepts It begs for a knowledge management system! • Documentation is important so that knowledge gained about a product and process is accessible and comprehensible to others involved in each stage of the lifecycle. • Information transparency and accessibility are fundamental tenets of the scientific method. 18
- 19. 2014 ISPE Annual Meeting PV Guide – Key Concepts A process flow diagram is the first step: • We recommend that firms diagram the process flow for the full-scale process. Process flow diagrams should describe each unit operation, its placement in the overall process, monitoring and control points, and the component, as well as other processing material inputs (e.g., processing aids) and expected outputs (i.e., in-process materials and finished product). 19
- 20. 2014 ISPE Annual Meeting Why E2500? E2500 Objective – “The overall objective is to provide manufacturing capability to support defined and controlled processes that can consistently produce product meeting defined quality requirements” 20
- 21. 2014 ISPE Annual Meeting Why E2500? Warning letters about controls and variability are on the rise: Numerous citations for: 21 CFR 211.110(a)Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. 21
- 22. 2014 ISPE Annual Meeting Significance of ASTM E2500 It’s all about manufacturing! “Application of the approach…is intended to satisfy international regulatory expectations in ensuring that manufacturing systems and equipment are fit for intended use, and satisfy requirements for design, installation, operation, and performance” ASTM E2500 §5.1 22
- 23. 2014 ISPE Annual Meeting Key concepts of ASTM E2500 - Risk-based approach The patient comes first! “The evaluation of risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient” ASTM E2500 §6.2.2.1 23
- 24. 2014 ISPE Annual Meeting Key concepts of ASTME E2500 - Science-based approach Knowledge is the practical use of information! “Product and process information, as it relates to product quality and patient safety, should be used as the basis for making science- and risk- based decisions that ensure that the manufacturing systems are designed and verified to be fit for their intended use.” ASTM E2500 §6.3.1 24
- 25. 2014 ISPE Annual Meeting Key concepts of ASTME E2500 - Science-based approach Collect the information in a central location: “Examples of product and process information to consider include: CQAs, CPPs, process control strategy information, and prior production experience.” ASTM E2500 §6.3.2 25
- 26. 2014 ISPE Annual Meeting Key concepts of ASTME E2500 - Critical system aspects Understand the critical aspects: “Critical aspects of manufacturing systems are typically functions, features, abilities, and performance or characteristics necessary for the manufacturing process and systems to ensure consistent product quality and patient safety.” ASTM E2500 §6.4.1 26
- 27. 2014 ISPE Annual Meeting Key concepts of ASTME E2500 - Quality by Design Think Cpk, Six Sigma! “Quality by design concepts should be applied to ensure that critical aspects are designed into systems during the specification and design process.” ASTM E2500 §6.5.1 27
- 28. 2014 ISPE Annual Meeting Key concepts of ASTME E2500 Specification, Design, Verification 28 Acceptance and release is just the beginning! H e r e b e d r a g o n s
- 29. 2014 ISPE Annual Meeting Key concepts of ASTME E2500 – Subject Matter Experts 29 SME is a relative term – “in the land of the blind…” “Subject Matter Experts are defined as those individuals with specific expertise and responsibility in a particular area or field (for example, quality unit, engineering, automation, development, operations…).” ASTM E2500 §6.7.1.
- 30. 2014 ISPE Annual Meeting Key concepts of ASTME E2500 – Subject Matter Experts 30 Shifts much of verification responsibility from the Quality unit to FSE SMEs “Subject Matter Experts should take the lead role in the verification of manufacturing systems as appropriate within their area of expertise and responsibility.” ASTM E2500 §6.7.2.
- 31. 2014 ISPE Annual Meeting Hurdles to Achieving E2500 • Traditionally, reducing the COGS for Pharma had relatively low impact to bottom line because of high margins for branded drugs • Global leadership effort has been focused more on marketing and development • Manufacturing was not considered a key competency • Requires culture change – leadership will back E2500 only when it grasps the concept… 31
- 32. 2014 ISPE Annual Meeting Motivators for Achieving E2500 • A warning letter or recall for product quality or patient safety can suspend operation causing drug shortages, loss of sales, loss of market, and/or damaged reputation • Better understanding and control of variability • Lower COGS • Achieve FDA targets of product quality and patient safety 32
- 33. 2014 ISPE Annual Meeting Tools for Implementing E2500 • Critical System Aspect Registry – Risk register linking Critical Systems, CQAs, CPPs, and risk to patient • Knowledge Management – Along with CSA Registry, collect tacit and explicit knowledge, including knowledge about process variability, in a transparent, searchable database organized by drug product and unit operation 33
- 34. 2014 ISPE Annual Meeting Tools Knowledge Management Why KM? • Knowledge is currently kept in silos, inaccessible to those who need it • MHLW (Japanese FDA) study in 2002 identified poor communication between R&D and manufacturing as one of the significant problems. – Dr. Yukio Hiyama • “The main competitive advantage organizations now have is the ability to transfer and apply knowledge.” Fred Miller, Kaleel Jamison Consulting Group, April 2012 34
- 35. 2014 ISPE Annual Meeting Tools Knowledge Management For current wisdom on implementing KM see supplement to PEM, May 2014 • http://www.ispe.org/multimedia/publications /Pharmaceutical_Engineering_Knowledge_Ma nagement/#/70/ 35
- 36. 2014 ISPE Annual Meeting Tools – Knowledge Management Don’t underestimate tacit knowledge: • Problem: low productivity across site due to “equipment” problems (eight parenteral fill-finish lines, five blow-fill-seal fill-finish lines and associated solution and suspension prep) • Approach: Held “brown-paper fair” to collect tacit information from operators and techs. • Result: 145 issues were identified, prioritized, and scheduled for remediation. Significant improvement in productivity. 36
- 37. 2014 ISPE Annual Meeting Tool – CSA Registry • The CSA Registry is a trace matrix that links CQAs, CPPs, and critical system aspects to risk to patient safety to help meet the intent of ASTM E2500. • Concept taken from Project Management Institute’s PMBOK Risk Register 37
- 38. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Identify enlightened sponsor with knowledge, authority, and responsibility • With sponsor, select an existing line/product to start with, one that is problematic, to get biggest returns, quickly. Think 80/20 rule and go after the low-hanging fruit, first. • This is a project – create a charter! 38
- 39. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Select team members with specific subject matter expertise with selected line and product, e.g.: – Product CQAs (development scientist) – Process CPPs (tech services) – Manufacturing critical systems (line manager) – FSE (engineering) – QMS (quality) • Train team members on CSA methodology 39
- 40. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Assign team members to collect product and process information: – CQAs (make sure they are current) – CPPs – Process flow diagrams and description 40
- 41. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Assign team members to collect line documentation – ETOPs with vendor docs, P&IDs, commissioning checklists, etc. – SLC documents - URS, FS, DS. – Verification documentation IQ, OQ, PQ, PV – SOPs and batch record templates – Operational information – system logs, CAPAs, OEE data, calibrations – Current or planned project work – Customer complaints, shortages, component inspection results, etc. 41
- 42. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Create a taxonomy that breaks lines into logical sections: e.g. cartridge filling line > filling machine > fill level control • With team members, identify the critical systems that are causing the most problems on the selected line 42
- 43. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Initiate an entry in the CSA Risk Register based on selected CQA and CSA (see slide #48): – Select a drug product CQA of interest (80/20 rule) – Identify a CSA that can impact that CQA (80/20 rule) – Document the acceptable range for the selected CQA at that point in the process – Is there PAT in place to directly monitor and/or control that CQA? 43
- 44. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • What is risk to patient? – Identify the associated hazard (risk to patient) – What is the risk to the patient if the CQA is OOS? Capture severity, probability, detectability. 44
- 45. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Continue to populate the registry with CPP information: – For the selected CSA, identify a CPP that can impact that CQA – Document the acceptable range for the selected CPP at that point in the process – Identify whether or not PAT exists for that CPP 45
- 46. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Control strategy – Describe the control strategy, both automated and procedural, including sampling inspections 46
- 47. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Perform risk management: – Perform Risk Management for each identified hazard/CSA combination focusing on how to minimize risk to patient – The common cause variation of the CSA may well be unknown. This could be the root cause of the problem and would have to be tested experimentally. Equipment manufacturers are usually very helpful here. 47
- 48. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Create CSA Registry Template (hypothetical example): 48 Line Unit Operation System Risk to patient (Hazard) Impacted CQA Acceptable range PAT Dental Cartridge Filling Bosch filler Oxygen in headspace 0.5 µg max no O2 in head space degrades epinephrine over time. Low epinephrine at time of administration causes anesthetic to wear off early resulting in pain to patient. CQA
- 49. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • Continue until you have worked through each CQA and each system in the line, prioritizing the 20% of the issues causing 80% of the problems. • Additional fields can be added, including: – Numerical risk evaluation for prioritizing – Associated CAPAs, deviations, customer complaints – Planned project work to address issue – Performance benchmarking to show improvements 49
- 50. 2014 ISPE Annual Meeting Tool - CSA Registry Methodology • End result is a better understanding of the line’s fitness for use along with risk mitigation strategies that can be prioritized for implementation and put into a maintenance or capital plan. • If retained in a searchable KM system, the Registry can be accessed for future change controls, CAPAs, continuous improvement, preventative maintenance, etc. 50
- 51. 2014 ISPE Annual Meeting Conclusion • Share your thoughts today and going forward! • Thanks to Nuala Calnan and Bill (Doc) Spanogle for their suggestions! • Andrew Faden, CPIP – [email protected] – [email protected] – 508 846 6700 cell 51